Patent GB-1030304-A (GB)
Title: Pregnane [3,2-c] pyrazoles
IPC: C07J17/00
Filed: 1963-02-26
Abstract: Novel steroids of the formulae <FORM:1030304/C2/1> <FORM:1030304/C2/2> (wherein R1 is hydrogen, fluorine, iodine, hydroxy, acyloxy, tetrahydropyranyloxy, methylsulphonyloxy or a dihydrogen phosphate radical or its alkali metal salt; R is hydrogen or an acyl, alkyl, aralkyl, cycloalkyl, aryl or heterocyclic radical which may be substituted; X is hydrogen or fluorine; Y is hydrogen, chlorine, fluorine or methyl; and the D 6-double bond is optional) and their 16a ,17a -acetals and ketals with aldehydes and ketones P.CO.Q (wherein P and Q are hydrogen, alkyl or aryl or are joined to form an alkylene chain) and salts thereof are prepared by reacting an 11-keto-16a ,17a -dihydroxy-21-acyloxy-4-pregnene-3,20-dione 20-ethylene ketal (which may also be substituted by the groups X and Y and a D 6 double bond) with an alkyl formate and sodium hydride to give the corresponding 2-hydroxymethylene derivative or its formate esters (the 21-acyloxy group is first hydrolysed), reacting this or the corresponding 2-alkoxymethylene compound (prepared by reaction with an alkanol and an acid catalyst) with hydrazine or a substituted hydrazine to give the [3,2-c] pyrazolo-steroid, removing any formate ester groups by treatment with sodium methoxide in methanol, reducing the 11-keto group to an 11b -hydroxy group, and removing the 20-ketal group with acid.  Alternatively the side-chain may be protected by converting an 11b ,16a ,17a -trihydroxy - 21 - acyloxy - 4 - pregnene - 3,20 - dione starting material to the corresponding 21-hydroxy - 16a ,17a  - acetal or ketal, converting this to the 21-tetrahydropyranyl ether, then converting this to the (3, 2-C) pyrazolo-steroid, and removing the 21-tetrahydropyranyl group and, if desired, the 16, 17-acetal or ketal grouping. The precise structure of the pyrazolo-steroid product, i.e. isomers when R is other than hydrogen, depends on whether the starting material is a 2-hydroxymethylene or 2-acyloxy-methylene compound, and the isomers may be separated by chromatography.  Products may be converted to other 16,17-acetals or ketals. They may also be converted to 21-acylates, and if 2 equivalents of an acylating agent are used on the N-unsubstituted compounds, the N-acyl-21-acylates are formed, from which the N-acyl group is selectively removed by heating with acetic acid.  21-Desoxy compounds may be prepared by converting the 21-ol (in which the N-atom is substituted and the 16,17-diol grouping is converted to an acetal or ketal) to the 21, mesylate, converting this to the 21-iodo steroid and reacting this with an alkali metal bisulphite. If the N-unsubstituted compound is used, this is converted to the 21-tetrahydropyranyl ether, this is N-acylated, the ether group is removed and the 21-ol converted to the 21-desoxy compound, and the N-acyl group finally removed.  The 21-fluoro compounds are prepared by heating the 21-mesylates with alkali metal fluorides; and the 21-dihydrogen phosphate esters are prepared from the 21-iodo compounds, silver phosphate and phosphoric acid, may be converted to the mono- or dialkali metal salts, from which the free phosphates may be obtained by contact with an ion-exchange resin. 21-Acyloxy starting materials and products may be hydrolysed to the corresponding 21-ols.  Numerous examples are given.  11 - Keto - 16a ,17a  - dihydroxy - 21 - acyloxy - 4 - pregnene - 3,20 - dione 20 - ethylene ketal compounds are prepared by converting 11b ,17a ,-21 - trihydroxy - 4 - pregnene - 3,20 - dione (which may be substituted by the groups X and Y) to the corresponding 21-acyloxy-D 5-3,20-bisethylene ketal, oxidizing this to the 11-ketone, dehydrating this to the D 16-derivative, hydroxylating this to the 16a ,17a -dihydroxy compound, and reconverting this to the D 4-3-one. 9a  - Fluoro - 11b ,21 - dihydroxy - 16a ,17a  - isopropylidenedioxy - 4,6 - pregnadiene - 3,20 - dione 21-acetate is prepared from the corresponding D 4-tetrol by reaction successively with acetone, acetic anhydride and chloranil.  Similarly are prepared 11b ,21-dihydroxy-6-methyl-16a ,17a -isopropylidenedioxy - 4,6 - pregnadiene 3,20 - dione 21-acetate and the 9a -fluoro derivative thereof. 6 - Chloro - 11b ,21 - dihydroxy - 16a ,17a  - isopropylidenediox - 4,6 - pregnadiene - 3,20 - dione 21-acetate is prepared from the corresponding 6-unsubstituted compound via the 6a ,7a -epoxide. The 9a -fluoro-6-chloro compound is prepared similarly. The 6-fluoro compounds are prepared similarly via the epoxides and D 4-6b -fluoro 7a -hydroxy compounds.  Steroids of the above general formulaeae wherein R1 is hydrogen, fluorine, hydroxy, acyloxy or a dihydrogen phosphate or its alkali metal salts are stated to have anti-inflammatory activity, and may be made up into pharmaceutical compositions with suitable diluents, carriers or coatings.